Our long-term goal is to develop a better understanding of central nervous system characteristics of persons at risk for alcoholism. Many Veteran alcoholics begin heavy drinking during their time in military service, and the VA is responsible for their care. Despite a large clinical literature on alcoholism, far less is known about the preclinical characteristics of persons at greatest risk for the disorder. In response to this information deficit, we instituted the Oklahoma Family Health Patterns Project to study nonabusing young adults with and without a family history of alcoholism. Persons with a positive family history are four times as likely to develop alcohol use disorders as those with no such history, and this risk doubles in persons who also have antisocial characteristics. Twin-adoption studies show that a tendency toward alcoholism and disinhibited and antisocial behavior traits that are coinherited. Persons with both a positive family history and personal evidence of behavioral disinhibition are accordingly considered to be at High Risk of future alcoholism, and those lacking these factors are considered at Low Risk. Our major hypothesis is that High Risk persons have altered brain mechanisms that serve to produce normal emotional responses to the environment and have deficient regulation of overt behavior. While evidence points to altered communication between the limbic system and prefrontal cortex, confirmatory neuroimaging is lacking. This application is subsumed under two aims: Aim I addresses altered affective reactivity associated with a high risk for alcoholism, and focuses on amygdala functional connectivity and anticipatory affective responses. Our discovery of amygdalar hypoactivation in High Risk persons viewing emotional faces suggests a possible deficit in affective response to social cues. A meaningful extension of this finding is to contrast the risk groups in functional amygdala connectivity. Inadequate processing of affective cues in High Risk persons may be consistent with a tendency to engage in risky behaviors and to subject themselves to negative consequences of drinking. We will examine group differences in specific connections, using the amygdala as the starting point of a network that includes the insula, the dorsal ACC, and the ventromedial PFC. The presence of amygdalar hypoactivation to emotional faces raises the question of how general this activation difference is. Therefore subjects will undergo a task that probes brain responses to anticipation of positive, negative, or neutral outcomes in a Pavlovian conditioning paradigm. This provides a second probe of emotional responsivity using a wider range of stimuli. We predict that the High Risk subjects will have less relative amygdala activation in anticipation of negative outcomes and greater relative activation in anticipation of positive ones in: caudate n., amygdala, ACC, and the insula. Aim II addresses disinhibited regulation of behavior associated with a high risk for alcoholism using three tasks that tap executive function, decision-making, and behavioral regulation. Executive controls will be tested using the Stroop response conflict task, sensitive to altered function in the cognitive control regions of the anterior cingulate gyrus, dorsolateral prefrontal cortex, and the left inferior precentral sulcus. Risky decision-making is examined using a delay discounting task examining functioning of the extended amygdala, nucleus accumbens, caudate, ventromedial prefrontal cortex, and ventral anterior cingulate gyrus. Behavioral disinhibition will be examined with a stop-signal task examining cognitive control regions of the anterior cingulate gyrus, dorsolateral prefrontal cortex, and the left inferior precentral sulcus. The planned studies are expected to yield new information concerning altered processing of emotional stimuli and behavioral disinhibition in young adults at high risk for future alcoholism. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health Treatment of alcoholism is a major health care cost for the VA system. Alcoholism often manifests in persons 18-30 years of age (Babor, Hofmann et al., 1992), a time that coincides with military service and perhaps combat exposure. As a result, the VA system is responsible for large numbers of veterans with alcohol and other substance use disorders that began during the period of active military service. Studies of persons at elevated risk for alcoholism can increase our knowledge of antecedent factors, contribute to models of alcoholism development, and aid in predicting who is most at risk.